This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Depressive disorders are a major health issue in the United States and cause severe social and economic problems. Currently, most of these disorders are treated with Selective Serotonin Reuptake Inhibitors (SSRIs) which cause an increase in serotonin levels in the synaptic cleft. How this increased availability of serotonin causes beneficial effects is not clear, however, it appears that it stimulates the synthesis of Brain-Derived Neurotrophic Factor (BDNF) which in turn enhances neurogenesis in the dentate gyrus of the hippocampus. It is thought that the formation of new connectivities of these neurons is, at least in part, responsible for successful treatment of depression. Thus, one goal is to identify the sites of actions as well as the mechanisms by which SSRIs cause an enhancement of BDNF levels in the hippocampus thereby stimulating neurogenesis. Many studies have shown that the frequency of depressive incidences increases in post-menopausal women and estrogen reduces depressive symptoms. Thus, a second goal is to identify the estrogen-sensitive neurons that project to the hippocampus and are regulated by serotonin and to reveal the mechanisms by which estrogen reduces the frequency and severity of depressive episodes. Aim 1: test the hypothesis that SSRIs and estrogen act on medial septal-diagonal band cholinergic neurons, the prefrontal cortex as well as directly on the hippocampus to enhance BDNF synthesis and neurogenesis in an additive or synergistic fashion. Aim 2: test the hypothesis that medial septal-diagonal band cholinergic neurons and cortical GABAergic neurons are necessary for estradiol and SSRIs to stimulate BDNF synthesis and neurogenesis in the hippocampus. Aim 3: test the hypothesis that the transcript-specific BDNF promoters and the untranslated regions regulate the expression, localization and function of BDNF.